Lipid droplet storage promotes murine pancreatic tumor growth

Abstract

Hypoxia Inducible Lipid Droplet Associated (HILPDA) is frequently overexpressed in tumors and promotes neutral lipid storage. The impact of Hilpda on pancreatic ductal adenocarcinoma (PDAC) tumor growth is not known. In order to evaluate Hilpda-dependent lipid storage mechanisms, expression of Hilpda in murine pancreatic cells (KPC) was genetically manipulated. Lipid droplet (LD) abundance and triglyceride content in vitro were measured, and model tumor growth in nu/nu mice was determined. The results showed that excess lipid supply increased triglyceride storage and LD formation in KPC cells in a HILPDA-dependent manner. Contrary to published results, inhibition of Adipose Triglyceride Lipase (ATGL) did not ameliorate the triglyceride abundance differences between Hilpda WT and KO cells. Hilpda ablation significantly decreased the growth rate of model tumors in immunocompromised mice. In conclusion, Hilpda is a positive regulator of triglyceride storage and lipid droplet formation in murine pancreatic cancer cells in vitro and lipid accumulation and tumor growth in vivo. Our data suggest that deregulated ATGL is not responsible for the absence of LDs in KO cells in this context.

Recent Advances on the Role of ATGL in Cancer

“…Notably, ATGL levels decrease with PEDF knockdown, suggesting that ATGL in pancreatic cancer may not have the same pro-metastatic ability as in breast cancer. Similarly, in another PDAC mouse model, inhibition of ATGL did not alter the difference in triglyceride abundance between Hilpda wild-type and knockdown cells ( 32 ). Therefore, in PDAC, ATGL may not be a critical factor in tumor proliferation and metastasis but might be a key factor in tumor formation.…”

“…Similarly, in pancreatic cancer cells, the bioinformatic analysis also revealed elevated expression of hypoxic lipid droplet-associated proteins ( 10 ). Moreover, in pancreatic ductal adenocarcinoma (PDAC) mouse model, HIG-2 was also found to increase the accumulation of LDs in cancer cells and promote the growth of cancer cells ( 32 ). Functionally, HIG-2 regulates fat storage in response to insufficient oxygen supply outside the cell or excess fatty acid content in the cell.…”

Lipid metabolism in pancreatic cancer: emerging roles and potential targets

“…Based on the double‐edged roles of LDs in multiple cancers, the influence of LDs on tumor growth and metastasis needs to be spelled out in the context of PC. Previous data showed that LDs were drastically increased in PC [ 57 ], and that LD accumulation was correlated with the tumor growth and aggressiveness [ 220 , 221 ]. Another study showed that the number of LDs in pancreatic CSCs was higher than that in non‐CSCs, and the peroxisome proliferator‐activated receptor α (PPARα) activation, which is considered a downstream factor of LD‐derived signaling, was observed in CSCs, implicating that LD‐PPARα axis is possibly involved in the maintenance of CSC properties [ 222 ].…”